Breast cancers in women 65-79 years old comprise over 50% of all newly diagnosed breast cancers, and yet known genetic and environmental risk factors account for a small percentage of risk. The majority of the recognized, modestly elevated risk factors for breast cancer in older women trace their etiologic importance to cumulative estrogen exposure. Other modestly elevated risk factors in older women, such as those associated with obesity, alcohol use, and physical inactivity, may be linked to breast cancer through stimulation of a chronically activated proinflammatory immune response that has direct cytotoxic or genotoxic effects. We will build on a completed study of breast cancer in older women (ages 65-79) to assess the possibility that single or multiple polymorphisms in the cytokine-driven inflammation pathways lead to an unbalanced immune response that favors uncontrolled cell proliferation and, over time, breast cancer. We hypothesize that 1) Variation in cytokine genes that favor a proinflammatory response are associated with an increased risk of breast cancer in older women, whereas those that favor an anti-inflammatory response are associated with a decreased risk. We will evaluate whether polymorphisms in proinflammatory (IL1, IL6, IL8, IL12, TNF, and leptin) and anti- flammatory (IL1RN, IL2, IL10, adiponectin) genes and their receptors alter the risk of breast cancer;2) The impact of specific gene-gene and gene-environment combinations alter the risk of breast cancer in older women (e.g., ligand-receptor pairs, IL6 and leptin, TNF and alcohol). As cytokines constitute the basic wiring that mediates the inflammatory response and since older women have different cytokine profiles compared to younger women that indicate a low-grade systemic inflammatory response, we propose that variation in cytokine genes are key players in translating exposures common in older women to risk factors for breast cancer and may provide insight into strategies for prevention in this age group, the women who are most at risk for breast cancer. Lay Summary: We plan to study the risk of postmenopausal breast cancer associated with cytokine genes that underlie a low-grade, chronic inflammatory response. Cytokine genes are expressed at different levels in older compared to younger women;therefore, we will also evaluate their contribution to breast cancer risk by levels of common exposures such as obesity and HRT use.